Germline TP53 mutations in women with very early onset breast cancer (BR)

Abstract

1015 Background: Women with Li-Fraumeni syndrome (LFS) have a 49% risk of cancer by age 30, most of which is BR. In small series of women with early BR, prevalence of germline TP53 mutation is 1% (age <40) or 4% (age <30), most with personal or family history suggesting LFS. If true prevalence were higher, clinical testing for TP53 mutations might be useful, as carriers are advised to avoid nonessential radiation due to 2nd cancer risk. Among women tested in our cancer genetics program, age at BR diagnosis was 33 years in female members of 38 TP53 mutation kindreds versus 41 yrs (p<0.0001) in 186 women with BRCA1 and 45 yrs (p<0.0001) in 65 women with BRCA2 mutations. Methods: The prevalence of germline TP53 mutations among women diagnosed with BR age ≤33 years was assessed. DNA was extracted from 165 cell lines from a population-based series of women with BR age ≤33 years in Connecticut and from whole blood from 45 similar women from the Dana-Farber/Harvard Cancer Center SPORE bank. Family history data came from questionnaires and could not be confirmed under the protocols. None met strict criteria for LFS, but 9 had histories consistent with Li-Fraumeni-Like (LFL) syndrome (see Table). TP53 analysis utilized high through-put techniques. Results: 3 germline mutations were identified in the cohort [prevalence 1.4%, 95% CI 0.3 to 4.1]. Among probands 1 had a mother with BR at 40, 1 a mother with BR at 59 and maternal grandmother with colon >70; the third had no family cancer history. There were no mutations among the 9 women with LFL. BRCA1/2 analysis results on the cohort will be available for ASCO. Conclusion: Routine screening for germline TP53 mutations in women with BR at unusually young ages will have a low yield in otherwise unselected patients. These data are consistent with Lallo et al, Lancet 2003. No significant financial relationships to disclose.